Novel methods

Abstract

Use of particular substituted heterocycle fused gamma-carboline compounds as pharmaceuticals for the treatment of agitation, aggressive behaviors, posttraumatic stress disorder or impulse control disorders.

1 . A method for the treatment of a disorder selected from agitation, aggressive behavior, posttraumatic stress disorder and impulse control disorder, comprising administering to a patient in need thereof an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein X is O, —NH or —N(CH 3 ); and Y is —O—, —C(H)(OH)— or —C(O)—, in free or pharmaceutically acceptable salt form. 
       
     
     
         2 . The method according to  claim 1 , wherein the compound of Formula I is selected from a group consisting of compounds of formula I wherein:
 X is —O— and Y is —C(H)(OH)—,   X is —NH— and Y is —C(H)(OH)—,   X is —N(CH 3 )— and Y is —C(H)(OH)—,   X is —O— and Y is —C(O)—,   X is —O— and Y is —O—,   X is —N(CH 3 )— and Y is —C(O)—,   X is —N(CH 3 )— and Y is —O—,   X is —NH— and Y is —C(O)—, and   X is —NH— and Y is —O—.   
     
     
         3 . The method of  claim 1  wherein X is —N(CH 3 )— and Y is —C(O)—. 
     
     
         4 . The method of  claim 1 , wherein the disorder is posttraumatic stress disorder. 
     
     
         5 . The method of  claim 1 , wherein the disorder is impulse control disorder. 
     
     
         6 . The method of  claim 5  wherein the impulse control disorder is intermittent explosive disorder. 
     
     
         7 . The method of  claim 1 , wherein the administration of the compound of Formula I is an adjunct to the administration of one or more additional antidepressants. 
     
     
         8 . The method of  claim 7 , wherein the administration of one of more additional antidepressants is an adjunct to administration of the compound of Formula I. 
     
     
         9 . The method of  claim 7 , wherein the antidepressant is selected from one or more of amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitaloprame, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenlzine sulfate, protiptyline, sertraline, tranylcypromine, trazodone, trimipramine, and venlafaxine, in free or pharmaceutically acceptable salt form. 
     
     
         10 . The method of  claim 7 , wherein the antidepressant is one or more antidepressants selected from selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants. 
     
     
         11 . The method of  claim 10  wherein the antidepressant is a SSRI. 
     
     
         12 . The method of  claim 1 , wherein the compound of Formula I is administered orally as a composition comprising a pharmaceutically acceptable diluent or carrier as an oral unit dose form that is a tablet, or capsule. 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein the effective amount of the compound of Formula I is a daily dose of about 10 mg to about 50 mg. 
     
     
         17 . The method of  claim 1 , wherein the effective amount of the compound of Formula I is a daily dose of about 20 mg to about 40 mg. 
     
     
         18 . The method of  claim 1 , wherein the effective amount of the compound of Formula I is a daily dose of about 1 mg to about 10 mg. 
     
     
         19 . The method of  claim 1 , further comprising administering one or more additional therapeutic agents selected from compounds that modulate GABA activity (e.g., enhances the activity and facilitates GABA transmission), a GABA-B agonist, a 5-HT modulator (e.g., a 5-HT1a agonist, a 5-HT2a antagonist, a 5-HT2a inverse agonist, etc.), a melatonin agonist, an ion channel modulator (e.g., blocker) a serotonin-2 antagonist/reuptake inhibitor (SARIs), an orexin receptor antagonist, an H3 agonist, a noradrenergic antagonist, a galanin agonist, a CRH antagonist, human growth hormone, a growth hormone agonist, estrogen, an estrogen agonist, a neurokinin-1 drug, and an antipsychotic agent, e.g., an atypical antipsychotic agent, in free or pharmaceutically acceptable salt form. 
     
     
         20 . The method of  claim 1 , further comprising administering one or more additional therapeutic agents selected from a group consisting of modafinil, armodafinil, doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazapam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem, gabaxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam, ketanserin, risperidone, eplivanserin, volinanserin (Sanofi-Aventis, France), pruvanserin, MDL 100907 (Sanofi-Aventis, France), HY10275 (Eli Lilly), APD125 (Arena Pharmaceuticals, San Diego, Calif.), AVE8488 (Sanofi-Aventis, France), repinotan, sarizotan, eptapirone, buspirone, MN-305 (MediciNova, San Diego, Calif.), melatonin, ramelteon (ROZEREM®, Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals, Rockville, Md.), PD-6735 (Phase II Discovery), agomelatine, lamotrigine, gabapentin, pregabalin, orexin, a 1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline), a benzamide derivative, Org 50081 (Organon—Netherlands), ritanserin, nefazodone, serzone, trazodone, Casopitant (GlaxoSmithKline), amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitaloprame, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protiptyline, sertraline, tranylcypromine, trazodone, trimipramine, velafaxine, chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine molidone, perphenazine, pimozide, prochlorperazine promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiparazole, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone, in free or pharmaceutically acceptable salt form. 
     
     
         21 . The method of  claim 1 , wherein the patient has not responded adequately to treatment with another antidepressant or combination of antidepressants. 
     
     
         22 . The method of  claim 20  wherein the patient has not responded to treatment with one or more antidepressants selected from selected from selective serotonin reuptake inhibitors (SSRIs)(e.g., selected from citalopram, escitalopram oxalate, fluoxetine, fluvoxamine maleate, paroxetine, sertraline, dapoxetine), serotonin-norepinephrine reuptake inhibitors (SNRIs)(e.g., selected from venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran, sibutramine), and tricyclic antidepressants. 
     
     
         23 . The method of  claim 22  wherein the patient has not responded to treatment with a SSRI. 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled)